Human intestinal epithelial cells express interleukin-10 through Toll-like receptor 4-mediated epithelial-macrophage crosstalk

Jinhee Hyun, Laura Romero, Reldy Riveron, Claudia Flores, Saravana Kanagavelu, Kristina D. Chung, Ana Alonso, John Sotolongo, Jose Ruiz, Armine Manukyan, Sally Chun, Gaurav Singh, Pedro Salas, Stephan R. Targan, Masayuki Fukata

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

In the intestine, interaction between epithelial cells and macrophages (M's) create a unique immunoregulatory microenvironment necessary to maintain local immune and tissue homeostasis. Human intestinal epithelial cells (IECs) have been shown to express interleukin (IL)-10, which keeps epithelial integrity. We have demonstrated that bacterial signaling through Toll-like receptor (TLR) 4 induces 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) synthesis in intestinal M's by cyclooxygenase (Cox)-2 expression. Here, we show that TLR4 signaling generates crosstalk between IECs and M's that enhances IL-10 expression in IECs. Direct stimulation of TLR4 leads to the expression of IL-10 in IECs, while the presence of M's in a Transwell system induces another peak in IL-10 expression in IECs at a later time point. The second peak of the IL-10 expression is two times greater than the first peak. This late induction of IL-10 depends on the nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ that is accumulated in IECs by TLR4-mediated inhibition of the ubiquitin-proteasomal pathway. TLR4 signaling in M's in turn synthesizes 15d-PGJ2 through p38 and ERK activation and Cox-2 induction, which activates PPAR in IECs. These results suggest that TLR4 signaling maintains IL-10 production in IECs by generating epithelial-M's crosstalk, which is an important mechanism in the maintenance of intestinal homeostasis mediated through host-bacterial interactions.

Original languageEnglish (US)
Pages (from-to)87-101
Number of pages15
JournalJournal of Innate Immunity
Volume7
Issue number1
DOIs
StatePublished - Dec 17 2015

Keywords

  • Epithelial cells
  • Interleukin-10
  • Intestine
  • Macrophages
  • Peroxisome proliferator-activated receptor
  • Toll-like receptors

ASJC Scopus subject areas

  • Immunology and Allergy

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    Hyun, J., Romero, L., Riveron, R., Flores, C., Kanagavelu, S., Chung, K. D., Alonso, A., Sotolongo, J., Ruiz, J., Manukyan, A., Chun, S., Singh, G., Salas, P., Targan, S. R., & Fukata, M. (2015). Human intestinal epithelial cells express interleukin-10 through Toll-like receptor 4-mediated epithelial-macrophage crosstalk. Journal of Innate Immunity, 7(1), 87-101. https://doi.org/10.1159/000365417